EGFR-TARGETED NANOEMULSIONS FOR IMAGING AND THERAPY OF OVARIAN CANCER -
DESCRIPTION (provided by applicant): Today 70% of patients with advanced ovarian cancer will achieve clinically complete remission with front line treatments of carboplatin and paclitaxel, unfortunately a majority these patients are destined to relapse and eventually die of disease within 12-18 months due to a persistence of chemoresistant cells. Diagnostic techniques for ovarian cancer include normal exam, monitoring CA-125 level and CT-scans all capable of observing gross changes in disease progression but are less sensitive at quantitating the number or location of chemoresistant cells. Our overarching strategy addresses the major failures of the front line therapy and diagnostics by using multifunctional nanoemulsions to target, image, and enhance cytotoxicity to simultaneously eradicate chemosensitive and chemoresistant tumor cells. Extending our positive rodent studies combining targeting, imaging and therapeutic in a single vehicle, these proposed studies will focus on engineering multifunctional nanoemulsions capable of: 1) Targeting EGFR expressing cells which is found on majority of ovarian cancers; 2) imaging disease regression or progression by delivering DPTA-Gd3+, an magnetic resonance imaging (MRI) contrast agent, directly to tumor cells; and 3) enhance the cytotoxicity of carboplatin by targeting but also by co-delivering the pro-apoptotic molecule C6-ceramide, shown to reestablish key apoptosis pathways to overcome chemoresistance. Preclinical studies will be carried out in human ovarian adenocarcinoma xenograft models in female nu/nu mice to identify key pharmacokinetics parameters, efficacy, and ability to image delivery efficiency and disease progression using MRI. Successful completion of these studies will guide Phase II studies to generate safety, pharmacokinetics, efficacy and scale-up manufacturing data to advance to clinical trials. Phase I outcomes will additionally encourage exploration of enhancing the targeted delivery of other chemotherapeutic drugs or other compounds that had not previously been evaluated clinically due to physical properties, bioavailability or toxicities.
PUBLIC HEALTH RELEVANCE: An estimated 22,000 new cases in 2008 and approximately 15,000 deaths in the United States, epithelial ovarian cancer is the most lethal of gynecologic cancers, due to its propensity to spread into the upper abdomen and beyond. Frontline lead to clinically complete remission in over 70% of patients, however typically within 12-18 months those patients relapse due to chemoresistant cells. Diagnostic techniques for ovarian cancer include normal exam, monitoring CA-125 level and CT-scans all capable of observing gross changes in disease progression but are less sensitive at quantitating the number or location of chemoresistant cells. Our overarching strategy addresses the major failures of the front line therapy and diagnostics by using multifunctional nanoemulsions to target, image, and enhance cytotoxicity to simultaneously eradicate chemosensitive and chemoresistant tumor cells.
